A number of related hormones make up the pancreatic polypeptide (PP) family. Pancreatic polypeptide was discovered as a contaminant of insulin extracts and was named more by its organ of origin, rather than functional importance (Kimmel, Pollock et al. Endocrinology 83: 1323-30, 1968). It is a 36-amino acid peptide [SEQ ID NO.: 1] containing distinctive structural motifs. A related peptide was subsequently discovered in extracts of intestine and named Peptide YY (PYY) because of the N- and C-terminal tyrosines (Tatemoto. Proc Natl Acad Sci USA 79: 2514-8, 1982) [SEQ ID NO.: 2]. A third related peptide was later found in extracts of brain and named Neuropeptide Y (NPY) (Tatemoto. Proc Natl Acad Sci USA 79: 5485-9, 1982; Tatemoto, Carlquist et al. Nature 296: 659-60, 1982) [SEQ ID NO.: 4].
These three related peptides have been reported to exert various biological effects. Effects of PP include inhibition of pancreatic secretion and relaxation of the gallbladder. Centrally administered PP produces modest increases in feeding that may be mediated by receptors localized to the hypothalamus and brainstem (reviewed by (Gehlert. Proc Soc Exp Biol Med 218: 7-22, 1998)).
Release of PYY [SEQ ID NO.: 2] occurs following a meal. An alternate molecular form of PYY is PYY[3-36] [SEQ ID NO.: 3] (Eberlein, Eysselein et al. Peptides 10: 797-803, 1989) (Grandt, Schimiczek et al. Regul Pept 51: 151-9, 1994). This fragment constitutes approximately 40% of total PYY-like immunoreactivity in human and canine intestinal extracts and about 36% of total plasma PYY immunoreactivity in a fasting state to slightly over 50% following a meal. It is apparently a dipeptidyl peptidase-IV (DPP4) cleavage product of PYY. PYY[3-36] is reportedly a selective ligand at the Y2 and Y5 receptors, which appear pharmacologically unique in preferring N-terminally truncated (i.e. C-terminal fragments of) NPY analogs. Peripheral administration of PYY reportedly reduces gastric acid secretion, gastric motility, exocrine pancreatic secretion (Yoshinaga, Mochizuki et al. Am J Physiol 263: G695-701, 1992) (Guan, Maouyo et al. Endocrinology 128: 911-6, 1991) (Pappas, Debas et al. Gastroenterology 91: 1386-9, 1986), gallbladder contraction and intestinal motility (Savage, Adrian et al. Gut 28: 166-70, 1987). The effects of central injection of PYY on gastric emptying, gastric motility and gastric acid secretion, as seen after direct injection in or around the hindbrain/brainstem (Chen and Rogers. Am J Physiol 269: R787-R792, 1995) (Chen, Rogers et al. Regul Pept 61: 95-98, 1996) (Yang and Tache. Am J Physiol 268: G943-8, 1995) (Chen, Stephens et al. Neurogastroenterol Motil 9: 109-116, 1997), may differ from those effects observed after peripheral injection. For example, centrally administered PYY had some effects opposite to those described herein for peripherally injected PYY[3-36] in that gastric acid secretion was stimulated, not inhibited. Gastric motility was suppressed only in conjunction with TRH stimulation, but not when administered alone, and was indeed stimulatory at higher doses through presumed interaction with PP receptors. PYY has been shown to stimulate food and water intake after central administration (Morley, Levine et al. Brain Res 341: 200-203, 1985) (Corp, Melville et al. Am J Physiol 259: R317-23, 1990).
Likewise, one of the earliest reported central effects of NPY [SEQ ID NO.: 4] was to increase food intake, particularly in the hypothalamus (Stanley, Daniel et al. Peptides 6: 1205-11, 1985). PYY and PP are reported to mimic these effects, and PYY is more potent or as potent as NPY (Morley, J. E., Levine, A. S., Grace, M., and Kneip, J. Brain Res 341: 200-203, 1985) (Kanatani, Mashiko et al. Endocrinology 141: 1011-6, 2000) (Nakajima, Inui et al. J Pharmacol Exp Ther 268: 1010-4, 1994). Several groups found the magnitude of NPY-induced feeding to be higher than that induced by any pharmacological agent previously tested, and also extremely long-lasting. NPY-induced stimulation of feeding has been reproduced in a number of species. Among the three basic macronutrients (fat, protein, and carbohydrate), the intake of carbohydrates was preferentially stimulated. No tolerance was seen towards the orexigenic effect of NPY, and when administration of the peptide was repeated over 10 days, a marked increase in the rate of weight gain was observed. Following starvation, the concentration of NPY in the hypothalamic PVN increased with time, and returned rapidly to control levels following food ingestion.
Pharmacological studies and cloning efforts have revealed a number of seven transmembrane receptors for the PP family of peptides, and these receptors have been assigned the names Y1 through Y6 (and a putative PYY-preferring receptor or Y7). Typical signaling responses of these receptors are similar to those of other Gi/Go-coupled receptors, namely inhibition of adenylate cyclase. Even with fairly low sequence homology among receptors, it is apparent that there is a clustering of amino acid sequence similarity between Y1, Y4 and Y6 receptors, while Y2 and Y5 define other families. Other binding sites have been identified by the rank order of potency of various peptides. The NPY-preferring receptor, which has not been cloned, has been termed Y3, and PYY-preferring receptors have also been shown to exist (putative Y7) (Reviewed in (Michel, Beck-Sickinger et al. Pharmacol Rev 50:143-50, 1998) (Gehlert, D. R. Proc Soc Exp Biol Med 218: 7-22, 1998)).
The Y5 and Y1 receptors have been suggested as the primary mediators of the food intake response (Marsh, Hollopeter et al. Nat Med 4: 718-21, 1998) (Kanatani, A., Mashiko, S., Murai, N., Sugimoto, N., Ito, J., Fukuroda, T., Fukami, T., Morin, N., MacNeil, D. J., Van der Ploeg, L. H., Saga, Y., Nishimura, S., and Ihara, M. Endocrinology 141: 1011-6, 2000). The prevalent idea has been that endogenous NPY, via these receptors, increases feeding behavior. Proposed therapies for obesity have invariably been directed toward antagonism of NPY receptors, while therapies for treating anorexia have been directed toward agonists of this ligand family (see, e.g., U.S. Pat. Nos. 5,939,462; 6,013,622; and 4,891,357). In general, PYY and NPY are reported to be equipotent and equally effective in all Y1, Y5 (and Y2) receptor assays studied (Gehlert, D. R. Proc Soc Exp Biol Med 218: 7-22, 1998).
The main characteristic of putative Y3 receptors is that they recognize NPY, while PYY is at least an order of magnitude less potent. The Y3 receptor represents the only binding site/receptor that shows a preference for NPY.
There is an additional binding site/receptor which shows preference for PYYs, termed PYY-preferring receptor, which is referred to herein as the Y7 receptor (s). Different rank orders of binding to this receptor, or class of receptors, have been reported, suggesting that there may be more than one receptor in this family. In most cases it has been applied to describe a receptor where PYY was three to five times more potent than NPY. The International Union of Pharmacology recommendations for the nomenclature of NPY, PYY and PP receptors are that the term PYY-preferring receptor is not used unless a potency difference of at least twenty fold between PYY and NPY is observed (Michel, M. C., Beck-Sickinger, A., Cox, H., Doods, H. N., Herzog, H., Larhammar, D., Quirion, R., Schwartz, T., and Westfall, T. Pharmacol Rev 50: 143-50, 1998). However, for purposes of this disclosure, reference to the Y7 receptor or pharmacology of a PYY-preferring receptor means a receptor having any degree of preference for PYY over NPY.
Obesity and its associated disorders are common and very serious public health problems in the United States and throughout the world. Upper body obesity is the strongest risk factor known for type 2 diabetes mellitus, and is a strong risk factor for cardiovascular disease. Obesity is a recognized risk factor for hypertension, atherosclerosis, congestive heart failure, stroke, gallbladder disease, osteoarthritis, sleep apnea, reproductive disorders such as polycystic ovarian syndrome, cancers of the breast, prostate, and colon, and increased incidence of complications of general anesthesia. (see, e.g., (Kopelman. Nature 404: 635-43, 2000)). It reduces life-span and carries a serious risk of co-morbidities above, as well disorders such as infections, varicose veins, acanthosis nigricans, eczema, exercise intolerance, insulin resistance, hypertension hypercholesterolemia, cholelithiasis, orthopedic injury, and thromboembolic disease (Rissanen, Heliovaara et al. BMJ 301: 835-7, 1990). Obesity is also a risk factor for the group of conditions called insulin resistance syndrome, or “Syndrome X.” Recent estimates for the medical cost of obesity and associated disorders are $150 billion worldwide. The pathogenesis of obesity is believed to be multifactorial but the basic problem is that in obese subjects nutrient availability and energy expenditure do not come into balance until there is excess adipose tissue. Obesity is currently a poorly treatable, chronic, essentially intractable metabolic disorder. A therapeutic drug useful in weight reduction of obese persons could have a profound beneficial effect on their health.
All documents referred to herein are incorporated by reference into the present application as though fully set forth herein.